Sulfonylbis(acylhydrazones) as anticholinesterase inhibitors: Synthesis, in vitro biological evaluation and computational studies

• Published in: Journal of molecular structure 2022-03, Vol.1252, p.132215, Article 132215
• Main Authors: Ibrahim, Muhamad, Latif, Abdul, Ahmad, Manzoor, Ahmad, Sajjad, Ali, Akbar, Siddique, Abu Bakar, Saadiq, Mohammad, Akbar, Nazia, farooq, Umar, Khan, Ajmal, Al-Harrasi, Ahmed, Ali, Mumtaz
• Format: Article
• Language: English
• Subjects: 4,4′-Sulfonyldiphenol; Acetylcholinesterase; Butyrylcholinesterase; Molecular docking; Molecular dynamics simulations; Sulfonylbis(acylhydrazones)
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.132215

This current research work is focused on the synthesis of sulfonyl-mediated hydrazones, its exploration as anticholinesterase inhibitors, in vitro biological evaluation, and computational studies. A series of 21 novel bis(acylhydrazones) (4a-u) have been synthesized in good to excellent yields using 4,4ꞌ-sulfonyldiphenol as the precursor. Characterization of the synthesized compounds was achieved via spectroscopic techniques i.e. UV, FT-IR, NMR (1H and 13C), and HRMS. In vitro anticholinesterase activity of these compounds was performed using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as cholinesterase enzymes. Among all the compounds tested, compounds 4 g and 4 h were found to be the most significant AChE inhibitions with IC50 values of 101.4 and 102.7 µM as compared to the standard cholinesterase inhibitor i.e., galantamine (IC50 = 104.5 µM). Additionally, compound 4 g was also found to be an excellent inhibitor of BChE with an IC50 value of 136.0 µM as compared to the standard galantamine (IC50 = 156.8 µM). Molecular docking of the most active compounds 4 g and 4 h also supported their potential to interact with cholinesterase enzymes. Further affirmation on the intermolecular stability of the docked complexes was achieved by molecular dynamics simulation for 100 ns with mean deviations ∼2 Å. Residue level fluctuations analysis also interpreted the good stability of compounds interacting pocket residues. Lastly, binding free energy analysis was performed that decipher the intermolecular interactions that are dominated by both van der Waals and electrostatic energies. In short, both theoretical and experimental studies unveiled the compounds as potent blockers of cholinesterase enzymes. •A series of 21 novel bis(acylhydrazones) (4a-u) have been synthesized.•Compounds 4 g and 4 h revealed significant AChE inhibitions.•Compound 4 g was also found to be an excellent inhibitor of BChE.•Molecular docking of 4 g and 4 h supported their potential to interact with enzymes.•Binding free energy analysis deciphers domination of van der Waals and electrostatic energies. [Display omitted]